PubMed · 8235580
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P Shubik. 1993-10-29. Carcinogenicity certification.. https://doi.org/10.1126/science.8235580
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MultiCASE has the ability to automatically determine the structural features responsible for the biological activity of chemicals. In the present study, 93 chemicals tested for their ability to induce chromosomal 'malsegregation' in the yeast Saccharomyces cerevisiae were analyzed. This 'malsegregation' mimics molecular events that occur during human development and carcinogenesis resulting in an effective loss of one chromosome of an autosomal pair and duplication of the homologue. Structural features associated with the ability to induce such chromosome loss and duplication were identified and compared with those obtained from examination of other toxicological data bases. The most significant structural similarities were identified between the induction of chromosomal malsegregation and several toxicological phenomena such as cellular toxicity, induction of sister chromatid exchanges in vitro and rodent developmental toxicity. Very significant structural similarities were also found with systemic toxicity, induction of micronuclei in vivo and human developmental toxicity. Less significant structural overlaps were found between yeast malsegregation and rodent carcinogenicity, DNA reactivity and mutagenicity, and the induction of chromosome aberrations in vitro and sister chromatid exchanges in vivo. These overlaps may indicate mechanistic similarities between the induction of chromosomal malsegregation and other toxicological phenomena. The predictivity of the SAR model derived from the present data base is relatively low, however. This may be merely a reflection of the small size and composition of the data base, however, further analyses suggest that it reflects primarily the multiple mechanisms responsible for the induction of chromosomal malsegregation in yeast and the complexity of the phenomenon.
Small Polydispersed Circular DNA (spcDNA) was suggested to be associated with genetically unstable cells. However, until now, qualitative and quantitative research has been limited due to the lack of efficient methods for detection and analysis. We developed a two-dimensional (2-D) neutral-neutral gel electrophoresis assay for the identification, characterisation and quantitation of spcDNA. Using this method, we established the relation of spcDNA to genetic and induced genomic instability in human cells, both in vitro and in vivo. Enhanced amounts of spcDNA were found in genetically unstable cells and tissues. spcDNA was detected in a tumor cell-line (HeLa) and in tumor tissue (colon carcinoma) as well as in fibroblasts derived from patients suffering from the genomic instability disease, Fanconi's Anemia. We failed to detect spcDNA in the genetically stable normal human fibroblasts. However, following treatment with the initiating carcinogen MNNG, an induction of spcDNA was observed. The level of spcDNA was quantified according to mitochondrial DNA (mtDNA) standards. In light of these findings, we discuss the possible role of spcDNA as a marker and an enhancer of genomic instability.
Recent evidence has linked cellular DNA repair capacity to the chemosensitivity of cancer cells to alkylating agents. Using single-cell gel electrophoresis ("comet assay"), we have analyzed the induction and differential processing of DNA damage in human lymphocytes derived from healthy donors and from patients with chronic lymphatic leukemia (CLL) after exposure to N-ethyl-N-nitrosourea in vitro. The extent of comet formation in lymphocytes after N-ethyl-N-nitrosourea exposure appears to depend predominantly on the processing of DNA repair intermediates, because strand breaks in plasmid DNA were not induced by ethylation before the addition of nuclear proteins. Although the initial level of a specific alkylation product (O6-ethylguanine) in nuclear DNA was uniform, different dose-response curves were obtained for the comet size in individual cell samples immediately after exposure, with small intercellular variation. The individual kinetics of DNA repair varied significantly between specimens derived from both healthy individuals and CLL patients; for the DNA repair half-time (t1/2), large difference was found. Pretreatment of cells with methoxyamine as a DNA repair modifier blocking the base excision repair pathway revealed a quite similar extent of base excision repair-independent DNA incision in almost all normal lymphocyte samples. In contrast, this portion varied relatively and absolutely to a great extent among individual samples of CLL lymphocytes, suggesting a loss of stringent control of DNA repair processes in these cells. The comet assay can thus be used to gain information about interindividual variation in the efficiency of different DNA repair processes in small samples of normal cells and their malignant counterparts.